Sphingomyelin and Related Sphingophospholipids
1. Structure and Occurrence of Sphingomyelin
Sphingomyelin or ceramide 1-phosphocholine consists of a ceramide unit with a phosphorylcholine moiety attached to position 1 of the sphingoid base component. It is thus the sphingolipid analogue of phosphatidylcholine, and like that lipid it is zwitterionic. The d18:1/16:0 molecular species is illustrated as an example.
Sphingomyelin is primarily of animal origin and is a ubiquitous component of all animal cell membranes, from mammals to nematodes (and in a few protozoa), where it is by far the most abundant sphingolipid. Indeed, it can comprise as much as 50% or more of the lipids in certain tissues, though it is usually lower in concentration than phosphatidylcholine. For example, it makes up about 10% of the lipids of brain, where it is a key constituent of myelin, but 70% of the phospholipids of the human lens. Like phosphatidylcholine, sphingomyelin tends to be in greatest concentration in the plasma membrane of cells (up to 20%) and especially in the outer leaflet. Thus, all the sphingomyelin in human erythrocyte membranes is in the outer leaflet, and ~90% of that in the plasma membrane of nucleated cells is in the outer leaflet. It is also abundant in the nucleus where it is the main phospholipid associated with chromatin, and in lysosomes, but there is very little in the endoplasmic reticulum (2 to 4%) and even less in mitochondria. All lipoprotein fractions in plasma contain appreciable amounts of sphingomyelin with a higher proportion in the VLDL/LDL. Sphingomyelin is the single most abundant lipid in erythrocytes of most ruminant animals, where it replaces phosphatidylcholine entirely. In this instance, there is known to be a highly active phospholipase A that breaks down the glycerophospholipids, but not sphingomyelin.
Sphingomyelin does not appear to occur in plants or fungi, which produce the sphingophospholipid ceramide phosphoinositol and related lipids instead, or in bacteria with rare exceptions, and its evolutionary significance is a matter for speculation. However, a number of bacteria and viruses utilize sphingomyelin or its metabolism in their hosts for growth and viability.
Sphingosine is usually the most abundant long-chain base constituent, together with sphinganine and C20 homologues, although other bases can be present, especially in ruminant animals. In contrast, sphinganine is the major sphingoid base in the sphingomyelin of human lens membranes, linked mainly to 16:0. Typically, the fatty acids are very-long-chain saturated and monounsaturated, including odd-numbered components. In comparison to the glycosphingolipids, 2-hydroxy acids are only rarely present, but they are found in testes, spermatozoa, kidney and skin sphingomyelin, for example. The absolute proportions of each fatty acid and sphingoid base can vary markedly between tissues and species, and some of the variability in compositions can be seen from the data in Tables 1 and 2.
Table 1. Fatty acid compositions of sphingomyelin (wt % of the total) in some animal tissues.
|Adapted from Ramstedt, B. et al. Analysis of natural and synthetic sphingomyelins using high-performance thin-layer chromatography. Eur. J. Biochem., 266, 997-1002 (1999); DOI.|
Table 2. Long-chain base compositions of sphingomyelin (wt % of the total) in some animal tissues.
|Also from Ramstedt, B. et al. Eur. J. Biochem., 266, 997-1002 (1999);
* d = dihydroxy base
Palmitic acid (16:0) is the most common fatty acid component of sphingomyelin in peripheral cells of mammals, while stearic acid (18:0) is more abundant in that of neural tissue, but this only hints at the potential complexity as there can be variability within tissues. For example, about 60% of the fatty acids of the sphingomyelin of the grey matter of human brain consist of stearic acid (18:0), while lignoceric (24:0) and nervonic (24:1) acids make up 60% of the corresponding lipid of white matter, although this is dependent on the stage of development. During the first two years of life, the 18:0 concentration in sphingomyelin of white matter decreases from 82% to 33%, while the proportions of 24:0 and 24:1 increase. This pronounced shift from long-chain to very-long-chain sphingomyelins is not observed in the cerebral cortex. Approximately 100 molecular species of sphingomyelin have been detected in human plasma. Although polyunsaturated fatty acids such as arachidonic acid are rarely present, they have sometimes been mistakenly identified in the literature. Exceptions are the sphingomyelins of testes and spermatozoa, which contain very-long-chain polyunsaturated fatty acids (up to 34 carbon atoms), the major components being 28:4(n-6) and 30:5(n-6) with a proportion having hydroxyl groups in position 2.
2. Biosynthesis, Metabolism and Function of Sphingomyelin
The biosynthesis of sphingomyelin is distinct from that of phosphatidylcholine and indeed depends upon it, as it involves transfer of phosphorylcholine from phosphatidylcholine to ceramide, synthesised in the endoplasmic reticulum, with liberation of 1,2-diacyl-sn-glycerols. The reaction is catalysed by a ceramide choline-phosphotransferase (sphingomyelin synthase or SMS) and takes place primarily in the Golgi but also in the plasma membrane, with two related enzymes each with six transmembrane domains and their N- and C-termini facing the cytosol, i.e. SMS1 and SMS2. Both enzymes are present in the Golgi, but only SMS2 is in the plasma membrane (facing the extra-cellular space in this instance) and may be necessary for the formation of raft domains (see below). SMS2 is also present in the membranes of nuclei from rat liver cells.
A specific ceramide transport molecule (CERT) is important to the reaction with SMS1 (see our web page on ceramides) in that it transfers ceramide from the cytosolic surface of the endoplasmic reticulum to the trans-Golgi in an ATP-dependent and non-vesicular manner. Much of the sphingomyelin produced in the Golgi is then delivered to the apical plasma membrane by a vesicular transport mechanism. Sphingomyelin synthesis is regulated in part by phosphatidylinositide metabolism and is connected to sterol homeostasis through the oxysterol binding protein (OSBP).
SMS2 in the plasma membrane is not dependent on CERT-mediated ceramide delivery, but is believed to convert ceramide produced locally by a sphingomyelinase back to sphingomyelin; this may be an important protective mechanism for the cell. The location of the enzymes explains the enrichment of sphingomyelin in specific membranes and the sidedness, i.e. the luminal trans-Golgi and the outer leaflet of the plasma membrane, while ceramide reaching the cis-Golgi is utilized for synthesis of glucosylceramide. In this instance, the nature of the molecular species of sphingomyelins produced differs appreciably from that of the ceramide precursors, suggesting considerable substrate specificity for the sphingomyelin synthases. The reaction can be reversible, using sphingomyelin to generating ceramide for specific signalling functions. It is evident that sphingomyelin biosynthesis forms a link between the sphingolipid signalling pathway (pro-apoptotic - see below) and that of glycerolipids via the mitogenic diacylglycerol by‑products, although the importance of this production relative to that via phosphatidylinositol is not known.
An alternative pathway of sphingomyelin synthesis has been demonstrated in the endoplasmic reticulum in which ceramide is first converted to ceramide phosphoethanolamine (see below) via transfer of the head group from phosphatidylethanolamine, followed by stepwise methylation of the ethanolamine moiety. However, the physiological significance of this pathway has yet to be established.
Membrane properties: It was long thought that the only function of sphingomyelin was to serve as a substitute for phosphatidylcholine as a building block of membranes, i.e. by forming a stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer. For example, it may limit the ingress of oxygen and thence oxidation of adjacent unsaturated acyl chains. While this is certainly one of its functions, the apparent similarity between phosphatidylcholine and sphingomyelin is superficial, and there are great differences in the hydrogen bonding capacities and physical properties of the two lipids. For example, sphingomyelin has an amide bond at position 2 and a hydroxyl on position 3 of the sphingoid base, both of which can participate in hydrogen bonding, while the trans double bond also appears to assist intermolecular interactions in membranes. Indeed, the first five carbon atoms of the sphingoid base in sphingolipids constitute a key feature that has been termed the ‘sphingoid motif’, which facilitates a relatively large number of molecular interactions with other membrane lipids, via hydrogen-bonding, charge-pairing, hydrophobic and van der Waals forces. With phosphatidylcholine, in contrast, the two ester carbonyl groups can act only as hydrogen acceptors. The degree of unsaturation of the alkyl moieties in each lipid is very different, and this gives them dissimilar packing properties in membranes.
It is now recognized that sphingomyelin and other sphingolipids have a strong tendency to interact with proteins and cholesterol, often via strong van der Waals interactions and hydrogen bonding, to form transient nano-domains in membranes known as 'rafts' (discussed in greater detail in a separate web page) and on the surface of lipoprotein particles. Initially, there was a view that saturated sphingomyelin formed a liquid-ordered phase with cholesterol or a gel phase with saturated ceramides to lead to lateral segregation within the membrane. A view has indeed been expressed that sphingomyelin and cholesterol metabolism are closely integrated, and in particular that the sphingomyelin concentration may control the distribution of cholesterol in cells. On the other hand, the understanding of the mechanism of raft formation in membranes has changed substantially in recent years, and while an interaction with cholesterol cannot be ruled out entirely, it can only be a minor factor.
Other functions: Sphingomyelin per se is generally considered to be a relatively inert molecule, although modern molecular biology methods are uncovering potential regulatory functions via interactions with particular proteins. For example, it has been shown to inhibit the activity of phospholipase A2α, a key enzyme in eicosanoid production. Sphingomyelin in the plasma membrane may be essential for the internalization of transferrin and thence of iron into cells, and it appears to be required for the activity of a number of membrane-bound proteins, including those of certain ion channels and receptors. As the most abundant sphingolipid in the nucleus, it is intimately involved in chromatin assembly and dynamics as well as being an integral component of the nuclear matrix. A single molecular species of sphingomyelin with a C18 acyl chain binds specifically to a coat protein designated 'p24' to enable it to form membrane vesicles. In addition, sphingomyelin is selectively recognized and acts as a receptor for the pore-forming toxins actinoporins, which are produced by sea anemones. There is increasing evidence of a role for sphingomyelin in the formation and function of ion channels.
There is a specific binding site for sphingomyelin on the amyloid beta-peptide (Aβ) in brain, and there is evidence from studies in vitro that this may promote the aggregation of these proteins in Alzheimer's disease. In turn, this leads to depletion of brain sphingomyelin by activation of acid sphingomyelinase with disruption of many protein–lipid interactions and thence of down-stream signalling pathways. In contrast, the ganglioside GM1 may have a protective role towards Aβ aggregation
As well as its role in membranes, it serves as a precursor for ceramides, long-chain bases and sphingosine-1-phosphate, together with many other biologically important sphingolipids, as part of the 'sphingomyelin cycle' (also termed the ‘sphingolipid’ or ‘ceramide’ cycles depending on the context). Some of these metabolites have functions as intra- and inter-cellular messengers, and others are essential membrane constituents. The sphingomyelin cycle extends to other sphingolipids via the action of sphingomyelinases and enzymes such as glycosylhydrolases and glycosyltransferases in cells to produce innumerable new oligoglycosylceramides. These molecular relationships are illustrated only briefly below, as most are discussed in detail on other pages on this site dealing with each lipid class.
In particular, sphingomyelin is a major source of ceramides in most cellular organelles, including the nucleus and even mitochondria, via the action of sphingomyelinases (see next section), and in addition to being a source of other sphingolipids these are required to trigger apoptosis and other metabolic changes. As ceramides do not mix well with glycerophospholipids and cholesterol, this conversion results in the formation of new membrane domains enriched in ceramide that exclude cholesterol and so differ in composition from other sphingolipid rafts. This has profound effects on membrane function, especially of the plasma membrane, in that different proteins may be recruited or excluded depending on their relative affinities for cholesterol and ceramides. It may also influence disease states such as cancer.
Chlamydiae, widespread bacterial pathogens, acquire sphingomyelin from the Golgi apparatus and plasma membrane of their hosts and this is necessary for the viability and growth of the organisms. Other pathogenic bacteria, notably Pseudomonas aeruginosa and Neisseria gonorrhoeae, can hijack sphingomyelin catabolic enzymes with deleterious effects upon the host. Likewise, human immunodeficiency virus (HIV) and the hepatitis C virus utilize host sphingomyelin for their own nefarious purposes.
Nutrition: Although there is no known nutritional requirement for sphingomyelin and other sphingolipids, they are a component of any diet containing egg, meat or dairy products. Thus, it has been estimated that per capita sphingolipid consumption in the United States, for example, is of the order of 0.3-0.4 g/d. As sphingolipids constitute an appreciable proportion of the polar lipid constituents of milk, they may be significant if minor nutrients for infants and beneficial effects upon their development have been claimed. From animal experiments, there is evidence that dietary sphingolipids can reduce the intestinal absorption of cholesterol and other lipids, leading to reductions in serum lipid concentrations. Feeding sphingolipids inhibits colon carcinogenesis and may alleviate some of the symptoms of inflammatory bowel disease. 2-Hydroxyoleic acid suppresses the growth and induces autophagy in cancer cells by stimulating the synthesis of sphingomyelin and increasing the amount of this lipid in the plasma membrane. On the other hand, plasma sphingomyelin levels are considered to be an independent risk factor for atherosclerosis.
3. Sphingomyelin Catabolism
Intestinal digestion: In contrast to the glycerolipids, dietary sphingolipids are not hydrolysed by pancreatic enzymes only. Rather, most of the sphingomyelin in the diet is hydrolysed in the brush border of the intestines by an alkaline sphingomyelinase (at a pH of 8.5–9 optimally) to ceramide and thence by a neutral ceramidase to free fatty acids and sphingosine. Some of this enzyme is also present in liver from which it is secreted in bile into the intestinal lumen where it can hydrolyse sphingomyelin and other phospholipids with the aid of bile salts. The sphingosine released at the brush border is absorbed, some is re-N-acylated and the remainder is converted via sphingosine-1-phosphate to palmitic acid, which is esterified into the triacylglycerol component of chylomicrons. In the process, some of the sphingolipid intermediates may have signalling functions and anti-inflammatory properties in intestinal cells. The alkaline sphingomyelinase is unusual in that is very different in its structure and other properties from intracellular enzymes with a related function; it is part of the (ecto)nucleotidepyrophosphatase-phosphodiesterase protein family (NPP) that includes autotaxin. The enzyme is believed to have a role in the production of sphingolipid metabolites within the intestines and colon especially, which may influence a number of disease states. For example, it appears to in inhibit colon cancer by generating ceramides. In addition, alkaline sphingomyelinase has phospholipase C activity towards the pro-inflammatory metabolite platelet-activating factor and towards lysophosphatidylcholine with potentially further beneficial effects. By reducing the level of endogenous sphingomyelin and increasing that of ceramides in the membranes of intestinal cells, it is believed to reduce the uptake of dietary cholesterol.
Catabolism in other tissues: The key enzymes for the degradation of sphingomyelin to ceramides in most tissues are also sphingomyelinases (phosphodiesterases), which are similar in function to phospholipase C and generate ceramides with their innumerable and important signalling properties as the main product. There are many such enzymes with different pH optima and metal ion requirements that operate in different regions of the cell with potentially distinct biochemical roles. Thus, there is an acid sphingomyelinase in the endo-lysosomes, and different neutral sphingomyelinases in the plasma membrane, endoplasmic reticulum, Golgi and mitochondria in addition to the alkaline sphingomyelinase in the intestines. It should not be forgotten that the other product of the reaction is phosphocholine, which has importance as a nutrient. Intriguingly, there is a sphingomyelinase in the bacterium Pseudomonas aeruginosa that can also act as a sphingomyelin synthase in vitro.
The lysosomal acid sphingomyelinase (pH optimum ca. 5) is expressed ubiquitously and has a key house-keeping role in maintaining normal membrane turnover and remodelling of the sphingolipid constituents. While other lysosomal sphingolipid hydrolases require a saposin activator protein for full activity, the acid sphingomyelinase incorporates a built-in N-terminal saposin domain so does not require an external activator. Under resting conditions, acid sphingomyelinase is stored inside lysosomes, but upon stimulation it undergoes vesicular transport to the plasma membrane where it docks with a specific protein and is exposed onto the outer leaflet. It then generates ceramide by hydrolysis of sphingomyelin and initiates the train of events that leads to apoptosis. There are reports that acid sphingomyelinase, by acting at the plasma membrane to produce ceramides, regulates the localization and trafficking of palmitoylated proteins from the Golgi, and it may also facilitate bacteria-host interactions. Experiments in vitro have demonstrated that the enzyme can be considered as a phospholipase C that is active against a wide range of phospholipids, including ceramide-1-phosphate and the unique lysosomal lipid bis(monoacylglycero)phosphate.
There is a related secreted acid sphingomyelinase (Zn2+-dependent), which can be transported to the outer membrane of the cell and is especially important in endothelial cells of the human coronary artery. This enzyme is produced by the same gene but differs from the lysosomal enzyme as it requires Zn2+ ions for activation and has a different glycosylation pattern. It can also operate at neutral pH and has multiple functions in that it is involved in many aspects of cellular signalling as well as in membrane sphingomyelin turnover. By acting at the plasma membrane to produce ceramides, it is believed to regulate the trafficking of palmitoylated proteins from the Golgi to their new location.
Neutral sphingomyelinases (pH optima 7.4), of which four quite distinct enzymes are known, are located in membranes of the endoplasmic reticulum, Golgi and plasma membrane with one in mitochondria (MA-NSM), where they have signalling functions by generating ceramides and thence other biologically active sphingolipids. Human NSM-1 has 423 amino acid residues and a molecular weight of 47.6 kDa; it has two putative transmembrane domains in the C-terminus and resides mainly in the nucleus and endoplasmic reticulum. It has a broad specificity for choline phospholipids but is most active with sphingomyelin and may not have a significant role in cellular signalling. In contrast, NSM-2 which is located in the Golgi apparatus and plasma membrane is activated by phosphatidylserine and is important for ceramide signalling. It appears to be especially important in brain and nervous tissue, where it is required for the secretion of hypothalamic releasing hormones, although it is relevant to many cellular functions and physiological processes in most other tissues. Dysregulation of NMS-2 appears to be a factor in many inflammation-related pathologies. Neutral sphingomyelinases-3 is found mainly in the plasma membrane of bone and cartilage, where it is vital for the process of mineralization; it is also important in striated and cardiac muscle. Little appears to be known of the function of the mitochondrial enzyme.
A diverse range of factors activate the enzymes, including chemotherapeutic agents, tumor necrosis factor-alpha, 1,25-dihydroxy-vitamin D3, endotoxin, gamma-interferon, interleukins, nerve growth factor, and most conditions known to induce cellular stress, especially in relation to inflammation. In that they generate ceramides and other sphingolipid metabolites that have important signalling functions from by far the most abundant sphingolipid in animal tissues, sphingomyelinases are believed to function as regulators of signalling mechanisms, especially in the nucleus of the cell. By this means, they influence disease states such as cancer. Thus, they have a much wider metabolic role than simply catabolism of sphingomyelin.
The type A and B forms of Niemann-Pick disease are lysosomal lipid storage disorders that are a consequence of a deficiency of acid sphingomyelinase with a resulting accumulation of sphingomyelin and smaller amounts of other sphingolipids, including gangliosides, in cells and tissues and especially in the monocyte/macrophage system to form the so-called “foam cells” that characterize the disease. A consequent lack of ceramide production may be involved in the pathology of the disease. Increasing sphingomyelin levels in turn result in elevated cholesterol concentrations. It is noteworthy that membranes containing ceramides have a much lower binding capacity for cholesterol, so sphingomyelin degradation may play a part in cholesterol homeostasis. Type C Niemann-Pick disease differs from the A and B forms and is caused by defects in two distinct cholesterol-binding proteins (NPC1 and NPC2).
4. Sphingosine phosphocholine
Sphingosine phosphocholine or 'sphingosine phosphorylcholine' or 'lyso-sphingomyelin' is found at trace levels only in tissues but has important biological properties. For example, it is released when platelet are activated and is present at concentrations of about 50 to 130 nM in plasma in association with the high-density lipoproteins mainly, from which it is believed to exert an influence upon the cardiovascular system. The levels are elevated in Niemann-Pick disease type C for which it is considered to be a biomarker together with an unusual lipid with some superficial structural and presumably functional similarity, now known to be N‑palmitoyl-O-phosphocholineserine (originally termed “lysosphingomyelin 509”, although it is not a sphingolipid and is better classified as a lipoamino acid). Sphingosine phosphocholine is also elevated in patients with the metabolic syndrome.
In skin, it is formed by the action of a sphingomyelin deacylase, where in excess it may have a role in atopic dermatitis, and it is probably produced by a similar route in some other tissues including heart, blood vessels, brain and the immune system. There is evidence that it is metabolized very rapidly in tissues, probably by a choline-specific glycerophosphodiester phosphodiesterase.
Sphingosine phosphorylcholine is a multi-functional lipid produced under physiological and pathological conditions that activates various signalling cascades affecting many cellular processes. For example, it may act as an extracellular agent through G protein-coupled receptors (sphingosine-1-phosphate receptors S1P1-5, GPR12 - but at low affinity), or as a second messenger to mediate intracellular Ca2+ release in various human tissues. By its effects upon cellular proliferation and differentiation, it is believed to stimulate the progression of many types of cancer, and it promotes the invasion of breast cancer cells in particular. In contrast, it has potent anti-inflammatory properties and reduces the level of organ dysfunction caused by bacterial lipopolysaccharide toxins in rats in vivo, for example, although some pro-inflammatory actions have also been described. While sphingosine phosphocholine has been reported to have many similar functions to sphingosine 1‑phosphate, the activities of the two lipids may not be easily distinguished as the former can be converted to sphingosine 1-phosphate by the action of the plasma enzyme autotaxin, also responsible for the biosynthesis of Alk-SMase does not share any structural similarity with NSMases or ASMases, belongs to the ectonucleotide pyrophosphatase/phosphodiesterase (NPP) family, and therefore is also known as NPP7 and is encoded by the ENPP7 gene. Following transcription, Alk-SMase is anchored on the surface of cell membranes, and in addition, it can also be released from this location by bile salts and pancreatic trypsin. Moreover, Alk-SMase accumulates in the gallbladder, and its activity depends on bile salts [39,40] and is thought to be mainly involved in hydrolyzing dietary SM and stimulating cholesterol absorption lysophosphatidic acid.
5. Other Sphingolipids Closely Related to Sphingomyelin
An unusual sphingolipid, 3-O-acyl-D-erythro-sphingomyelin, has been found in plasma of the newborn pig and infant (but not in that of adults). In this instance, position 3 of the sphingosine residue is linked to an additional fatty acid (C16 or C18) via an ester bond (alkali-labile). The cyanobacterium Scytonema julianum contains sphingomyelin with an acetyl group esterified to an ω-1 hydroxyl of a long-chain fatty acid.
A phospholipase D in the venom of the brown spider converts sphingomyelin to a cyclic phosphate by an intramolecular transphosphatidylation reaction with the potential to disrupt membranes. Sphingolipids have been found in a species of earthworm with phosphorylcholine linked to the carbohydrate moiety rather than directly to ceramide of mono- and digalactosylceramides (see our web page on monoglycosylceramides).
6. Ceramide Phosphoethanolamine and Other Sphingophospholipids
Ceramide phosphoethanolamine, the sphingolipid analogue of phosphatidylethanolamine, is a component of the lipids of insects, some fresh water invertebrates and many species of bacteria (where it is often accompanied by ceramide phosphoglycerol), but it is present at trace levels only in mammalian cells (300 to 1,500-fold below those of sphingomyelin). As an example, it is one of the main sphingolipid in Drosophila melanogaster, where d14:1 and d16:1 are the main long-chain bases; it has an important role in the functional equivalent of myelin to ensheath axons where it replaces galactosylceramide, which is a major component of myelin in mammals. It is apparently able to do this because the two lipids have similar physical properties. There are obvious differences in the charged state, but both lipids have a high phase transition temperature and tight packing, and neither is miscible with cholesterol.
In insects, CDP-ethanolamine is the donor of the head group for ceramide phosphoethanolamine synthesis (akin to phospholipid biosynthesis by the Kennedy pathway). However, in mammalian cells, it is produced at very low levels in the endoplasmic reticulum mainly by all members of the sphingomyelin synthase family, which are bifunctional, and it never accumulates in membranes. There is also a distinctive synthase, termed 'SMS related protein' because of its structural similarity to the sphingomyelin synthase, which is active in brain especially, but its main function is to act as a phosphatidylethanolamine phospholipase C.
A few bacterial species produce ceramide phosphoethanolamine and these include Bacteroides fragilis, a prominent member of the human gut biome. In Sphingobacterium spiritivorum, the type species of genus Sphingobacterium, ceramide phosphoethanolamine is accompanied by ceramide phosphoinositol and ceramide phosphomannose, with branched-chain base (mainly iso-17:0) and fatty acid (mainly iso-15:0) components. Ceramide phosphoethanolamine has also been fully characterized in three species of plant fungal pathogens (Oomycetes); the fatty acid and long-chain bases components vary with species, and for example one contains phytosphingosine and another an unusual branched-trienoic base. A phosphonolipid analogue is found in certain organisms. In addition to ceramide phosphoethanolamine, the protozoan parasite Trypanosoma brucei contains sphingomyelin and ceramide phosphoinositol.
Ceramide-1-phosphate and ceramide phosphoinositol are particularly important sphingo-phospholipids and as such have their own web pages here. Ceramide phosphoglycerol has long been known as a constituent of the membranes of anaerobic bacteria of the genus Bacteriodes. Unusual forms of it, including dihydroceramide phosphoglycerol and a form with two fatty acid components in an estolide linkage (illustrated), are the most abundant lipids in the oral Gram-negative pathogen Porphyromonas gingivalis.
In this instance, it has sphinganine (dihydrosphingosine) or an iso-methyl-branched sphinganine as the long-chain base with an amide linkage to 3-hydroxy-iso-methylhexadecanoic acid, the hydroxyl group of which is esterified to iso-methyltetradecanoic acid. It is believed to make a significant contribution to the virulence of the organism in dental decay.
Ceramide phosphomannose has been identified and characterized in the lipids of the bacterium Sphingobacterium spiritivorum, the type species of genus. Like the other sphingolipids in this species, the ceramide unit contains 15‑methylhexadecasphinganine and 13‑methyltetradecanoic acid primarily.
These compounds stimulate murine macrophages via a Toll-like receptor to effect bacterial clearance, and interestingly there are specific requirements for both the long-chain base and fatty acid components of the ceramide for this activity.
In addition to acetylated sphingomyelin, the cyanobacterium Scytonema julianum contains an acylacetylglycerol phosphoacetylated glycolipid that exhibits a biological activity very similar to that of platelet-activating factor. A second type of glycosphingophospholipid is known in which glycosphingolipids are further phosphorylated, i.e. where the ceramide is linked directly to carbohydrate moieties not via phosphate, are known from earth worms and the model nematode Caenorhabditis elegans, and these are discussed in relation to their parent glycosylceramides.
Sphingomyelin is readily isolated from animal tissues by adsorption chromatography (TLC and HPLC), although peaks or bands can split into two or three poorly resolved fractions. This is due in part to the changes in hydrophobicity resulting from the wide range of chain lengths in the fatty acid constituents, and in part to the presence of 2-hydroxy acids. As with other sphingolipids, the amide bond is resistant to mild alkaline hydrolysis, so special methods are required for analysis of the fatty acid and sphingoid base components. Molecular species of the intact lipid can be resolved by reversed-phase HPLC, but another useful approach is to hydrolyse to the less polar ceramides with the enzyme phospholipase C, after which the ceramides can be analysed either by reversed-phase HPLC or by high-temperature GC. Nowadays, mass spectrometric methods in conjunction with HPLC or direct-inlet (‘shotgun’) methods with electrospray ionization are being used increasingly for the analysis of sphingomyelin and other sphingolipids.
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